To collect information about the wide spectrum of mitochondrial diseases, NAMDC has designed and implemented a comprehensive NAMDC Mitochondrial Disease Clinical Registry, which gathers baseline clinical, biochemical, and molecular genetic data as well as tracks the natural histories of the patients through the NAMDC Clinical Longitudinal study. The overall missions of the NAMDC Registry are to: better understand the phenotypes of mitochondrial diseases; enable genotype/phenotype correlations; facilitate enrollment into clinical studies under NAMDC and other entities; and characterize natural histories of select mitochondrial diseases. More than 1,379 patients have been enrolled across 17 NAMDC sites in collaboration with the United Mitochondrial Disease Foundation (UMDF). New features added to the Registry include a Remote Recruitment program and a data mining tool for NAMDC investigators. We have also created NAMDC Research Diagnostic Criteria for mitochondrial diseases with strict benchmarks for definite, suspected, or unlikely levels of diagnoses. Samples of blood, urine, and other tissues are being deposited into the NAMDC Biorepository housed at the Mayo Clinic. The NAMDC Clinical Registry, Research Diagnostic Criteria, and Biorepository are three pillars that form a strong foundation for multi-center collaborative mitochondrial disease research. From this firm base, productive patient-oriented projects have already sprouted: a review of the NAMDC Registry data; 4 natural history studies (pyruvate dehydrogenase complex (PDC) deficiency, mitochondrial neurogastroIntestinal encephalomyopathy, Alpers syndrome, and Pearson syndrome); 6 survey studies; and 9 pilot studies. This project seeks: to expand the NAMDC Clinical Registry and Biorepository; to apply and refine the NAMDC Research Diagnostic Criteria; to characterize at least 6 specific mitochondrial conditions; to continue the Clinical Longitudinal study; to develop novel NAMDC Registry-wide natural history studies; to provide material for genomic testing of molecularly undefined NAMDC Registry subjects (Project 2); to strengthen links to mitochondrial disease sequence data resource (MSeqDR) consortium; to support development and utilization of new mitochondrial functional assays (Project 3); to support the advanced genetic and newborn screening studies of PDC deficiencies (Project 4); and to identify patients for the expanded access study of deoxynucleoside therapy for thymidine kinase 2 deficiency (Project 5).